Comparative study of dulaglutide single-use pen Ateos versus insulin degludec FlexTouch on learning and mock administration time in Japanese patients with type 2 diabetes mellitus - a post-hoc analysis.

Aims: Clinical data have shown that patients with diabetes require shorter training time to use Ateos versus FlexTouch. Using data acquired from a previous study, self-administration procedures that necessitated more time and repetition during mock injection were evaluated.Methods: In this open-label task- and interview-based crossover study, 48 self-injection naïve participants with type 2 diabetes mellitus (T2DM) were randomized to 1 of 2 sequences to perform a mock injection of Ateos and FlexTouch into a rubber pad after receiving training. Time needed to conduct mock injection steps (preparation, pre-injection set-up, injection, clean-up), and the number and time needed for repeated steps due to procedural errors, were measured as post-hoc analyses.Results: Mean time for preparation, injection, and clean-up was shorter for Ateos (13, 15, 9 s) versus FlexTouch (96, 53, 36 s). Overall time for administration including repeated steps was 75 s for Ateos and 288 s for FlexTouch. Nine participants repeated procedures due to errors when using Ateos (preparation: 6; pre-injection set-up: 2; injection: 1), and 7 participants when using FlexTouch (preparation: 2; pre-injection set-up: 2; injection: 5). There was 1 repeat per person for Ateos injections versus multiple repeats for FlexTouch injections.Conclusions:Post-hoc analysis demonstrates the time needed for overall administration was shorter for Ateos than FlexTouch, and time for each procedure was shorter or similar for Ateos versus FlexTouch. Ateos was easy for participants with T2DM to learn with fewer repeated steps due to procedural errors, and easy for healthcare professionals to introduce to their patients.

Diabetes care providers' manual for disaster diabetes care.

To ensure that experiences and lessons learned from the unprecedented 2011 Great East Japan Earthquake are used to improve future disaster planning, the Japan Diabetes Society (JDS) launched the "Research and Survey Committee for Establishing Disaster Diabetes Care Systems Based on Relevant Findings from the Great East Japan Earthquake" under the supervision of the Chairman of the JDS. The Committee conducted a questionnaire survey among patients with diabetes, physicians, disaster medical assistance teams (DMATs), nurses, pharmacists, and nutritionists in disaster areas about the events they saw happening, the situations they found difficult to handle, and the needs that they felt required to be met during the 2011 Great East Japan Earthquake. A total of 3,481 completed questionnaires were received. Based on these and other experiences and lessons reported following the 2011 Great East Japan Earthquake and the 2004 Niigata-Chuetsu Earthquakes, the current "Manual for Disaster Diabetes Care" has been developed by the members of the Committee and other invited authors from relevant specialties. To our knowledge, the current Manual is the world's first to focus on emergency diabetes care, with this digest English version translated from the Japanese original. It is sincerely hoped that patients with diabetes and healthcare providers around the world will find this manual helpful in promoting disaster preparedness and implementing disaster relief.

Diabetes Care Providers' Manual for Disaster Diabetes Care.

To ensure that experiences and lessons learned from the unprecedented 2011 Great East Japan Earthquake are used to improve future disaster planning, the Japan Diabetes Society (JDS) launched the "Research and Survey Committee for Establishing Disaster Diabetes Care Systems Based on Relevant Findings from the Great East Japan Earthquake" under the supervision of the Chairman of the JDS. The Committee conducted a questionnaire survey among patients with diabetes, physicians, disaster medical assistance teams (DMATs), nurses, pharmacists, and nutritionists in disaster areas about the events they saw happening, the situations they found difficult to handle, and the needs that they felt required to be met during the 2011 Great East Japan Earthquake. A total of 3,481 completed questionnaires were received. Based on these and other experiences and lessons reported following the 2011 Great East Japan Earthquake and the 2004 Niigata-Chuetsu Earthquakes, the current "Manual for Disaster Diabetes Care" has been developed by the members of the Committee and other invited authors from relevant specialties. To our knowledge, the current Manual is the world's first to focus on emergency diabetes care, with this digest English version translated from the Japanese original. It is sincerely hoped that patients with diabetes and healthcare providers around the world will find this manual helpful in promoting disaster preparedness and implementing disaster relief.

Effects of the calcineurin inhibitors cyclosporine and tacrolimus on bone metabolism in rats.

Immunosuppressive therapy is considered as one of the factors inducing to the onset of osteoporosis after organ transplantation. Chronic immunosuppressive therapy after transplantation is required for organ transplant patients, and it is important to prevent the occurrence of osteoporotic fractures to maintain the quality of life in patients. In this study, we examined the effects of cyclosporine and tacrolimus on bone metabolism in rats. Five-week-old male Wistar rats were treated orally with 15 mg/kg cyclosporine or 1.5 mg/kg tacrolimus daily for 4 weeks. Each of cyclosporine and tacrolimus significantly reduced the bone strength of the femoral mid-diaphysis and bone mineral density of the tibia and femur. Bone histomorphometry showed that the administration of both drugs resulted in a decrease in bone volume, number and thickness of trabeculae, and an increase in trabecular separation. Bone formation parameters such as osteoid volume, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate significantly increased in the cyclosporine-treated group. Bone resorption parameters such as eroded surface, osteoclast surface, and osteoclast number significantly increased in both the cyclosporine- and the tacrolimus- treated groups. These results showed that cyclosporine increases both bone formation and bone resorption, leading to a high-turnover bone loss, and that tacrolimus increases bone resorption without affecting bone formation, leading to bone loss.

Comparative usability study of the dulaglutide single-use pen versus the insulin degludec FlexTouch® among self-injection-naïve patients with type 2 diabetes mellitus in Japan.

OBJECTIVE: This study assessed training time with the dulaglutide single-use pen (SUP) and the insulin degludec disposable prefilled pen (FlexTouch®) in self-injection-naïve patients with type 2 diabetes mellitus (T2DM) in Japan. METHODS: This multi-center, open-label, comparative, crossover study measured training time with the dulaglutide SUP vs FlexTouch®. Participants learned how to use both devices in a randomly assigned order. Healthcare providers (HCP) conducted the training. The primary end-point was the time required to train self-injection-naïve T2DM participants to self-inject correctly using each device. Secondary end-points included performance measures, such as success and error rates, patient perceptions related to ease-of-use, and factors associated with training time and performance. RESULTS: Overall, 48 participants were randomized and completed the study. The mean training time to achieve correct administration was significantly shorter with the dulaglutide SUP vs FlexTouch® (7.4 min vs 19.7 min, p < .001). The proportions of participants who successfully completed the mock injection without error were similar for both devices. Ninety-two percent (44/48) of participants reported that the dulaglutide SUP was easier to use than FlexTouch®. CONCLUSIONS: In this study, participants required a shorter training time to achieve correct administration with the dulaglutide SUP, and had a higher preference for the dulaglutide SUP, when compared to FlexTouch®. These data suggest that the dulaglutide SUP is easy-to-use, which may decrease the burden on HCPs to train diabetic patients how to administer injection therapy and reduce patient injection hurdles, such as needle fear.

Characterization of Novel Insulin Fibrils That Show Strong Cytotoxicity Under Physiological pH.

Amyloid fibrils are ß-sheet-rich protein aggregates that are associated with more than 20 diseases. Insulin is known to form amyloid fibrils under a variety of conditions in vitro. Insulin fibrillations have been generally performed under acidic conditions, which are conducive to the formation of fibrils. As insulin is found almost exclusively as a monomer in acidic solutions, insulin fibrillation under acidic conditions is proposed to occur via its monomer. However, insulin fibrils, which cause injection-localized amyloidosis, form under neutral pH conditions in vivo, because both subcutaneous tissue and almost all insulin formulations maintain a neutral pH. In this study, we induced fibrillation under conditions more closely resembling physiological conditions than those used in previous studies with the aim of better understanding the nature of injection-localized amyloidosis in vivo. The results of transmission electron microscopy, structural analyses, and MTT assay show that the fibrils formed under conditions more closely resembling physiological conditions have different properties from the fibrils described to date. The results of this study indicate that fibrils formed under conditions more closely resembling physiological conditions have different properties from insulin fibrils induced under the conditions reported in previous studies.

Comparison of clinically relevant technical attributes of five insulin injection pens.

BACKGROUND: Insulin injection pens are the predominant devices for insulin delivery in Europe and Japan because of their ease of use and convenience. This study compared clinically relevant technical attributes of durable insulin pens that are important to people with diabetes, specifically functions relating to cartridge-fitting, dose-setting, and dose-delivery on NovoPen® 4, ClikStar®, HumaPen Luxura®, Itango®, and Biosulin® Pen. METHODS: Frequency components and duration of audible clicks on dose setting and injection were measured using audio equipment when setting and delivering 20 IU of insulin. To assess cartridge-fitting torque, each pen was attached to a torque gauge via the attached needle, and torque was measured with each 180° turn as the cartridge was screwed into the body of the pen. Rotary torque of the dose-setting dial was measured when setting the dose to the maximum dose unit of the pen. Injection force was measured when delivering 20 IU at 5 mm/s in a vertical position and at a tilt of 14.7° from vertical. RESULTS: Audible clicks on dose-setting and dose-delivery were most distinguishable on NovoPen 4, while NovoPen 4 and ClikStar had generally lower cartridge-fitting torque and injection (both vertical and angled) force values. CONCLUSION: Overall, the results showed that durable insulin pens such as NovoPen 4 have useful features related to assembly, dose-setting, and injection, which may facilitate ease of use for diabetes patients, particularly elderly patients and those with visual and/or manual dexterity impairments.

A comparison of the handling and accuracy of syringe and vial versus prefilled insulin pen (FlexPen).

BACKGROUND: To determine the preferable method for self-injecting insulin, we compared the handling, safety, and dose accuracy of a conventional disposable syringe and vial with FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark), a prefilled pen. METHODS: Insulin therapy-naive healthcare professionals (HCPs) (n = 30), unfamiliar with insulin delivery, injected 10 U of insulin into a sponge pad using either a syringe and vial or the FlexPen, both with 30-gauge 8-mm needles, on day 1. The following day, they used the alternative method. They evaluated the handling of the two methods on device-specific questionnaires and compared overall preference on a third questionnaire. To evaluate dose accuracy, 30 insulin therapy-experienced HCPs and 20 insulin therapy-naive HCPs were asked to deliver 10 U of insulin using each method, and the amount discharged was weighed. RESULTS: FlexPen was rated easier to use and overall more preferable than the syringe and vial by insulin therapy-naive HCPs (P < 0.001). The pen device was more accurate than the syringe and vial when used by experienced HCPs (mean +/- SD dose delivered, 9.91 +/- 0.11 U vs. 9.82 +/- 0.25 U, respectively; P < 0.001) and by insulin therapy-naive HCPs (9.91 +/- 0.12 U vs. 9.74 +/- 0.85 U; P < 0.001). CONCLUSIONS: Insulin therapy-naive HCPs found FlexPen easier to handle and preferable to use compared to a conventional syringe and vial. Both insulin therapy-experienced and -naive HCPs were able to deliver insulin significantly more accurately with the FlexPen than with a syringe and vial (P < 0.001).

[Pharmacokinetic monitoring of 5-fluorouracil may improve the clinical benefit with an individualized regimen-a case report].

Serum levels of 5-fluorouracil(5-FU)were measured in a patient receiving pharmacokinetic modulation chemotherapy( PMC), with 5-FU, as well as a combination of oxaliplatin and infusional 5-FU plus leucovorin(FOLFOX). A 77- year-old man presented with unresectable multiple hepatic metastases after abdominoperineal resection of rectal / carcinoma, and was successfully treated by PMC. The patient initially received infusional 5-FU at 750 mg/m(2) once a week, and showed a partial response. Serum 5-FU levels were higher at night, and the peak concentration of 5-FU was / 398 ng/mL. After 13 months of PMC, second-line chemotherapy with FOLFOX was initiated because new liver metastases had appeared. After 4 cycles of FOLFOX4, progression was observed, and the concentration profile of 5-FU / was measured. The area under the concentration vs. time curve(AUC ngxh/mL)was smaller with FOLFOX4 than with PMC, so the FOLFOX6 regimen was tried instead. The AUC increased and disease progression was suppressed. This case shows that individual adjustment of the dose and regimen based on pharmacokinetic monitoring can increase the clinical benefit of fluorouracil.

Comparison of intuitiveness, ease of use, and preference in two insulin pens.

BACKGROUND: The intuitiveness, instruction time, and handling of the Levemir (insulin detemir) FlexPen and the Lantus OptiClik pen (with insulin glargine) were investigated. METHODS: This randomized open-label crossover study involved two groups of insulin-device-naive Japanese patients with type 2 diabetes [mean (SD) age 61.9 +/- 12.3 years, 57% male]. Patients were evaluated on the ease-of-use of each insulin pen without instruction [intuitiveness group (n = 32)], or with instruction [instruction time group (n = 29)]. Patient preferences for the respective devices were assessed by questionnaire. RESULTS AND DISCUSSION: FlexPen required significantly less instruction time (p < .001) and was objectively more intuitive to use (p < .001) than OptiClik. Nevertheless, few patients in the intuitiveness group felt confident injecting either pen prior to instruction (FlexPen, 31%; OptiClik, 16%). No patients in the instruction time group found FlexPen difficult to learn, whereas 45% of patients found OptiClik difficult or very difficult to learn. FlexPen was rated simpler to use (77% versus 12%; p < .001), easier to inject (67% versus 13%; p < .001), and more convenient (71% versus 12%; p < .001) compared with OptiClik. More patients would trust FlexPen to deliver insulin injections (p < .01) and would prefer to use FlexPen compared with OptiClik (82% versus 13%; p < .001). CONCLUSIONS: FlexPen was faster to teach, simpler to use, and more trusted by patients compared with OptiClik. Mean injection time was significantly shorter for FlexPen than OptiClik, with or without instruction. This study highlights not only how easy it is for patients to learn to use FlexPen, but also how easily health care providers can teach patients to use it.

[Team-based medical care can improve tailor made chemotherapy for colorectal cancer].

We report that team-based medical care has an important role in tailor made chemotherapy for colorectal cancer. We organized a chemotherapy support team to facilitate the early detection of toxicity and to get hold of therapeutic needs in individual patients. We also measured the circadian variation of 5-fluorouracil plasma concentrations to permit tailor dosed chemotherapy. To date, the chemotherapy support team has managed the performance of pharmacokinetic modulating chemotherapy in 30 patients with unresectable or recurrent colorectal cancer. The median survival time was 19 months after the first-line chemotherapy and 14 months after the second-line treatment. Our results suggest that team-based medical care is practically useful for tailor made chemotherapy in patients with colorectal cancer.

Patient acceptance and issues of education of two durable insulin pen devices.

BACKGROUND: Insulin pen devices offer patients a more convenient, accurate, and discreet mode of insulin delivery than traditional syringes and vials. This open-label, randomized, comparative crossover study assessed patient preference for two reusable pens: NovoPen 4 (Novo Nordisk A/S, Copenhagen, Denmark) and OptiClik (Sanofi-Aventis, Bridgewater NJ). METHODS: Thirty-five diabetes patients with no previous experience of pen devices (mean age 56.7 years; range 17-80 years; 57% male) used both pens to deliver a 10 unit saline dose into an injection cushion. Half received guidance according to official instruction manuals, and half were given no instructions. Learning times were also measured. Participants completed a detailed questionnaire to determine their preferences. RESULTS: Overall, 32 of 35 participants preferred NovoPen 4 compared with two of 35 for OptiClik (91.4% vs. 5.7% respectively, P<0.001), and one had no preference. NovoPen 4 was significantly favored over OptiClik in almost all questionnaire criteria, including safety (P<0.001), size of pen (P<0.001), appearance (P<0.001), and ease of use (P<0.001). The majority of patients were able to use NovoPen 4 without guidance (94.4%) compared with just over half for for OptiClik (55.6%, P<0.01). Learning time was also significantly faster for NovoPen 4 (62.6 s) than for OptiClik (95.8 s) (P<0.05). CONCLUSIONS: Patients learned how to use both pens quickly (under 2 min), but NovoPen 4 was preferred by participants over OptiClik. Patient acceptance of a pen device may support insulin initiation, particularly in type 2 diabetes.

Dosing accuracy of two insulin pre-filled pens.

OBJECTIVE: This study was designed to determine the dose accuracy of two commonly available insulin pre-filled pens for use in diabetes - FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark) (FP) and SoloStar (Sanofi-Aventis, Paris, France) (SS). RESEARCH DESIGN AND METHODS: Dosing accuracy was tested at 5 U, 10 U and 30 U doses - three previously unused pens of both pre-filled pens were used for each dose. At the 5 U dose each pen was tested 42 times, at the 10 U dose each pen was tested 25 times and at the 30 U dose each pen was tested 9 times. The pre-filled pens were used strictly according to manufacturers' instructions and measurements were made on a sensitive balance and corrected for the specific density of the insulin formulations used. Specified limits were based on ISO standards (+/-1 U for the 5 U and 10 U doses and +/-1.5 U for the 30 U dose). RESULTS: FP was more accurate for injecting 5 U, 10 U and 30 U doses (absolute mean 4.95 +/- 0.19 U, 9.61 +/- 0.27 U and 29.70 +/- 0.34 U, respectively) than SS (absolute mean 4.86 +/- 0.39 U, 9.27 +/- 0.52 U and 28.73 +/- 0.47 U, respectively). No doses were outside specified limits for 5 U and 30 U with FP and 1.3% of doses were outside these limits at the 10 U dose. For SS; 1.6%, 29.3% and 33.3% of doses were below the pre-specified threshold for the 5 U, 10 U and 30 U doses, respectively. CONCLUSIONS: This non-blinded comparison indicates that FP is a more accurate insulin pre-filled pen than SS at three different insulin doses. In this single-user study, FP delivered consistent and accurate doses of insulin but SS had a high frequency of under dosing. No assessment was made of user variability in this study.

Usability of a microtapered needle (TN3305) for insulin treatment in japanese patients with diabetes mellitus: a comparative clinical study with a standard thin wall needle.

BACKGROUND: We evaluated the clinical usability of a microtapered needle (TN3305, "Needle T," Terumo Corp., Tokyo, Japan) by comparing it with a standard needle (Micro-Fine +, 31 gauge, 5 mm, thin wall, "Needle B," Nippon Becton Dickinson Co., Ltd., Tokyo) in a multicenter study. METHODS: Ninety-nine patients with diabetes mellitus being treated in 11 Japanese hospitals were enrolled in the study. Written consent was obtained from all patients. They were allocated randomly to two groups by an envelope (crossover) method. Injections were performed using one needle first, followed by the other needle 4 or 5 days later. Pain caused by injection was evaluated using a visual analogue scale (VAS). RESULTS: In the overall evaluation, Needle T was chosen by 40 patients (44.4%) and Needle B by 17 (18.8%); 33 patients (36.7%) expressed no preference. VAS scores for Needles T and B were 1.48 +/- 0.18 and 2.47 +/- 0.24 cm, respectively (P < 0.001). In this study, lower VAS indicated less pain. CONCLUSIONS: The preferences and VAS scores suggested that Needle T caused less pain than Needle B. The incidence of adverse events and safety were equivalent for both needles. We believe that usability of Needle T by patients for self-injection is better.

Assessment of dose selection attributes with audible notification in insulin pen devices.

BACKGROUND: Patients with type 2 diabetes often suffer from impairments in vision as well as manual dexterity. The purpose of this study was to assess the reliability of dose selection and setting of five insulin devices by patients using auditory and sensory confirmation. METHODS: A total of 48 patients (30 men, 18 women; mean +/- SD age 60.5 +/- 14.0 years; hemoglobin A(1c) 8.7 +/- 1.9%) were randomized to test the following devices: NovoPen 3 (Novo Nordisk A/S, Bagsvaerd, Denmark), HumaPen Ergo (Eli Lilly, Indianapolis, IN), Humalog Pen (Eli Lilly), InnoLet (Novo Nordisk), and FlexPen(Novo Nordisk). RESULTS: Significantly more patients detected an auditory confirmation of dose setting when using the NovoPen 3 compared with the Humalog Pen (P < 0.001), HumaPen Ergo (P < 0.001), and InnoLet (P < 0.01). The audible click for the FlexPen was also heard by more patients than for the Humalog Pen (P < 0.001) and HumaPen Ergo (P < 0.01). All patients found that the Flex- Pen provided physical sensory confirmation; the percentage was higher than for those using the Humalog Pen (P < 0.001), HumaPen Ergo (P < 0.001), and InnoLet (P < 0.01). The NovoPen 3 was also associated with a higher percentage of patients who felt the click sensation than with the Humalog Pen (P < 0.001) and HumaPen Ergo (P < 0.01). Patients reported more confidence in setting the correct dose with the NovoPen 3 and FlexPen, and found these the most reliable for dose setting. Sound recordings showed that the NovoPen 3 produced the loudest clicks when setting a dose (P < 0.001 for all comparisons). CONCLUSIONS: The clarity of the click when setting a dose on an insulin delivery device can affect the patient's confidence in selecting the correct dose.

FlexPen: addressing issues of confidence and convenience in insulin delivery.

BACKGROUND: In people with type 1 or type 2 diabetes, poor adherence to insulin therapy can compromise disease management. There are several reasons for poor adherence, including social embarrassment, inconvenience, needle anxiety, fear of injection pain, and complicated regimens. Attempts to facilitate implementation of insulin therapy and to improve treatment adherence have focused on expanding the choices and features of insulin delivery devices. OBJECTIVE: This review addresses the features, advantages, and disadvantages of insulin pen devices, with particular reference to FlexPen (Novo Nordisk, Bagsvaerd, Denmark), a prefilled/disposable pen device. METHODS: Data from clinical studies published through June 2005 that evaluated the safety or efficacy of FlexPen in patients with type 1 or type 2 diabetes were reviewed. Key studies were selected following assessment of the sponsor's reference collection and as a result of MEDLINE searches (key words: FlexPen and pen devices). Particular attention was paid to studies comparing the FlexPen device with other pen devices. Peer-reviewed journal articles and published conference papers were included in the evaluation, as were reviews addressing the general use of these devices in the treatment of diabetes and associated issues. RESULTS: Up to 65% of patients with type 1 or type 2 diabetes are not confident in their ability to effectively self-manage their disease. Only 23% of people with type 2 diabetes believe that insulin therapy would help them to better manage their disease. As many as 25% of people with diabetes who require insulin describe some anxiety regarding self-injection. Other barriers to effective insulin therapy include fear of injection pain, weight gain, and hypoglycemia; feelings of failure and guilt; and lack of motivation. CONCLUSIONS: Insulin pen devices are discreet and offer patients convenience and flexibility. These features may give patients the confidence to overcome issues of needle anxiety and the social embarrassment associated with self-injection and, therefore, may lead to improved adherence to recommended insulin dosing schedules and compliance with multiple-injection regimens.